(i) Field of the Invention
The invention relates to the production of new drugs, particularly eutrophic drugs, the active principle of which consists of transferrins. The invention is of particular significance for human therapy. However it is not limited thereto. It may also be applicable in veterinary medicine.
(ii) Description of Related Art
An eutrophic drug means a drug that is capable of maintaining or restoring the structure and function of tissue and cells in the person's body, particularly when that person undergoes treatments with other drug principles which beyond the favourable clinical effects which they may exert, are also fraught with undesirable side effects, particularly are liable of seriously injuring healthy cells and tissue of the body. Thus no matter how valuable the drug, difficulties may be encountered in monitoring its use in patients heavily in need for it. Such type of drugs shall hereinafter be referred to as "cytotoxic drugs".
An example of such cytotoxic drugs is cyclosporin which, as is well known, can also induce in the treated host muscular and functional disabilities accompanied by severe pains and/or nephrotoxicity that can ultimately produce renal dysfunction in the patient, for instance as evidenced by falls in glomerular filtration rates.
The dramatic side effects of antitumor drugs are well known. Similarly, anti-inflammatory drugs can entail a full array of damages ranging from gastric diseases to general disturbance of the metabolism in the treated patient.
There is thus a strong need to for a drug composition capable of overcoming the side effects of cytotoxic drugs, particularly to either prevent the tissue or cell degradation or promote the repair of damaged cells and tissue, more generally of assisting the natural principles which in the body participate to the eustasis.
The eutrophic drug of the composition of the invention is characterized in that its active principle consists of transferrins.
Although not always compulsory, the transferring should originate from the same mammal as the treated one. Thus human transferring should be the preferred active principle of eutrophic drugs for use in man.
Transferrins as such are a class of two-sited, single chain, metal-binding proteins, widely distributed in physiological fluids and cells of vertebrates.
Each transferrin consists of a single polypeptide chain, of molecular weight in the range 76000-81000, which contains two similar but not identical binding sites.
If the shape of human serum transferrin is approximated by an ellipsoid of revolution, then the ratio of major radii to minor is 2:1 for iron-saturated transferrin, and increases to 2.5:1 or 3:1 when the protein is freed from iron.
The isoelectric point of serum transferrin is on the acid side of neutrality.
The transferring are all glycoproteins.
Human serum transferrin contains about 5% carbohydrate, linked to the protein in two identical and nearly symmetrical branched heterosaccharide chains. it has a molecular weight of about 80000. 1 mg of the iron-saturated protein contains about 1.4 .mu.g iron.
The complete amino acid sequence of human plasma transferrin has been established by at least three groups using CNBr cleavage (CNBr) and by complementary DNA (cDNA) methods (MacGillivray, RTA, et al. "The complete amino acid sequence of human serum transferrin", Proc. Natl. Acad. Sci. USA 79, 2504-2508, 1982 and Uzan G. et al. "Molecular cloning and sequence analysis of cDNA for human transferrin" Biochem. Biophys. Res. Commun. 1990, 273-281, 1984 and Yang F. et al. "Human transferrin: cDNA characterization and chromosomal localization" Proc. Natl. Acad. Sci. USA 81, 2752-2756, 1984). It is composed of 678 amino acid residues, which together with the two-N-linked oligosaccharide chains exhibit a calculated molecular weight of 79,570 (of which 6% is contributed by the glucosidic moiety: MacGillivray, RTA et al. and Uzan G. et al., "Molecular cloning and sequence analysis of cDNA for human transferrin" Biochem. Biophys. Res. Commun. 119, 273-281, 1984). Williams J. ("The evolution of transferrin", Trends Biochem. Sci. 7, 394-397, 1982) has suggested the importance of sulfhydryl groups in stabilizing the iron-binding site and has traced their evolutionary developement to the 17 disulfides found in human transferrin.
For a general review of the status of general knowledge about transferrins see the general publication titled "The physiology of transferrin and transferrin receptors" by Helmut A. Huebbers and Clement A. Finch in Phyiological Reviews, vol. 67, n.degree. 2, Apr. 1987.
Procedures for obtaining transferrin, particularly transferrin of human origin in a biologically pure state have been disclosed in that publication. Preferred purification procedures are either based on physico-chemical based separation steps followed by selective fixation on matrix-bound antibody or matrix-bound receptor.